Chapter 21 Neuroimmunological disorders

Chapter 21 Neuroimmunological disorders

2014 Ch21 2/12/03 11:42 am Page 101 Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2) The Human Hypothalamus: Basic and Clinical Aspects...

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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2) The Human Hypothalamus: Basic and Clinical Aspects, Part II D.F. Swaab, author © 2004 Elsevier B.V. All rights reserved

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CHAPTER 21

Neuroimmunological disorders

21.1. Neurosarcoidosis of the hypothalamus

led to the diagnosis of schizophrenia, schizoaffective disorder and dementia. Also, mental status associated with delirium, euphoria, depression, aggression, apathy and cognitive deficits have been described. If neurosarcoidosis occurs, it has a striking predilection for the hypothalamus and pituitary, i.e. in 10–26% of cases (Robert, 1962; Turkington and Macindoe, 1972; Stern et al., 1985; Vanhoof et al., 1992; Oksanen, 1994; Guoth et al., 1998; Schielke et al., 2001). Central diabetes insipidus occurs in about 25% of patients with neurosarcoidosis (Bullmann et al., 2000) and can be the first manifestation of the disease (Konrad et al., 2000). Hyperprolactinaemia may be present (Molina et al., 2002). Other manifestations of hypopituitarism are hypoglycemia, dwarfism, panhypopituitarism, hypogonadism, obesity, and weight gain or weight loss (Bell, 1991; Murialdo and Tamagno, 2002; Randeva et al., 2002). Symptoms also attributed to hypothalamic involvement in sarcoidosis are somnolence, insomnia, hypothermia, extreme variations in body temperature, intolerance to cold, anorexia, hyperphagia, and progressive obesity and personality changes (Robert, 1962; Branch et al., 1971; Bell, 1991; Sommer et al., 1991; Vanhoof et al., 1992). In addition, a patient with hypothalamic sarcoidosis was described who had polyuria, inappropriate vasopressin (VP) release and excessive thirst. The patients fitted the criteria of Schwartz–Bartter (Chapter 22.6a) and the neurosarcoidosis was confirmed by autopsy (Kirkland et al., 1983). Up to 20% of neurosarcoidosis patients have psychiatric manifestations. These can range from mild apathy to severe mental deterioration (Vanhoof et al., 1992; O’Brien et al., 1994). In addition, memory loss associated with confusion has been described (Sharma, 1997). A 67-year old woman who had neurosarcoidosis, which damaged the anteromedial hypothalamus with an

The etiology of sarcoidosis is unknown. Environmental factors, infectious agents or hereditary factors may be involved. The seasonal clustering reported for various types of sarcoidosis (Wilsher, 1998) suggests that circannual fluctuations in the immune system or in infections may be important. Melatonin may mediate circannual immunological fluctuations (Nelson and Demas, 1997). Since a patient developed neurosarcoidosis 22 years after augmentation mammoplasty through the injection of silicone gel (Yoshida et al., 1996), it has been suggested that immunomodulations by foreign bodies such as silicone may also be a pathogenic risk factor in sarcoidosis. (a) Clinical presentation Neurological involvement is rather rare; it occurs in about 5% of the sarcoidosis patients and leads to death in 12–18% of all cases (Vanhoof et al., 1992; O’Brien et al., 1994; Sharma, 1997). Criteria for the diagnosis of possible, probable and definitive neurosarcoidosis have been proposed (Zajicek et al., 1999). Neurosarcoidosis may be confused clinically with multiple sclerosis, Lyme disease, Bechet’s disease, histiocytosis-X, Wegener’s granulomatosis, Whipple’s disease, lymphomatosis, meningeal carcinomatosis and a variety of infections, including cryptococcal meningitis, tuberculosis, syphilis, toxoplasmosis, and fungal infections. The diagnosis of isolated neurosarcoidosis, can only be established by biopsy (Graham and James, 1988; Sommer et al., 1991; Zajicek et al., 1999; Randeva et al., 2002; Chapters 20.1, 21.3). In addition, neurosarcoidosis has 101

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extension into the mamillary bodies, did not only have hyperphagia and hyperdipsia, but also had severe memory failure, characterized by spontaneous confabulations, disorientation and severely impaired free recall with preserved recognition. The authors argued that damage of the anterior hypothalamus rather than of the mamillary bodies was responsible for the confabulary amnesia (Ptak et al., 2001). The exact role of hypothalamic and other lesions in the psychiatric symptoms (see Chapter 26) has to be better defined. The optic nerve is, after the facial nerve, the second most commonly involved cranial nerve in neurosarcoidosis. MR images may show optic nerve enhancement. The characteristic picture is that of an atypical optic neuritis often subacute in onset, which might recover following steroids or cause permanent visual impairment (Zajicek et al., 1999). The optic nerve is affected in some 5% of the patients with sarcoidosis (Sharma and Anders, 1985; Stern et al., 1985; Graham and James, 1988; Westlake et al., 1995; Fig. 21.1). The optic chiasm is also frequently affected (Walker et al., 1990). Space-occupying sarcoid lesions may lead to papilledema and optic nerve atrophy (Sharma and Anders, 1985; Katz et al., 2003). Most of the cases in which sarcoidosis is manifested as an optic nerve tumor were mistaken for optic nerve meningioma (Macafee et al., 1999). Diplopia has also been reported (Molina et al., 2002). One case has been described that presented in a very unusual manner, with anosmia and visual changes. Noncaseating granulomata were subsequently found in the respiratory epithelium and submucosal (Kieff et al., 1997). Once an association was described between a Rathke’s cleft cyst and sarcoidosis lesions scattered around it, causing an intra- and extracellular mass and hypopituitarism without diabetes insipidus (Cannavò et al., 1997). Sudden death resulting from hypothalamic sarcoidosis has been reported a few times. In one case, autopsy revealed neurosarcoidosis with secondary hydrocephalus. The other case was a 23-year-old woman who had experienced 6 months of amenorrhea and a 50-pound weight gain. She had an extensive infiltration of the hypothalamus, including the pituitary stalk, the median eminence/infundibular nucleus, the right optic nerve, mamillary bodies, the supraoptic nucleus and the walls of the third ventricle, including the paraventricular nucleus (PVN). The PVN showed a marked cell loss. Death was proposed to be due to the loss of PVN neurons that innervate autonomic centers, leading to cardiopulmonary arrest (Gleckman et al., 2002).

(b) Pathology Neurosarcoidosis is due to noncaseating granulomas infiltrating the hypothalamus (Graham and James, 1988; Bell, 1991). The granulomas are initially made up of loosely organized epithelioid cells derived from macrophages that are surrounded by a ring of T-lymphocytes. In older granulomas large numbers of epithelioid and giant cells are surrounded by a small number of lymphocytes (Bell, 1991). Around the granulomas nerve cells may disappear, demyelination and gemistocytic reactive astrocytes are found (Robert, 1962). In addition, space-occupying sarcoid lesions can be found at the base of the brain and in the floor of the third ventricle. They may also manifest themselves as a pituitary pseudotumor (Robert, 1962; Timsit et al., 1993) or, e.g. Rathke’s cleft cyst (Cannavò et al., 1997). Whereas earlier postmortem findings pointed mainly to partial or total destruction of the pituitary by granulomas, later examination of both the pituitary and the hypothalamus showed extensive and preferential infiltration of the hypothalamus by granulomatous inflammation or granulomas, and little, if any, involvement of the pituitary itself (Bell, 1991; Fig. 21.2). Autopsy was only performed on a few patients with neurosarcoidosis and showed granulomata diffusely scattered in the median eminence and bilaterally throughout the hypothalamus (Selenkow et al., 1959; Turkington and MacIndoe, 1972). In addition, late stages of hyalinized granulomata have been reported throughout the hypothalamus. They consisted of multiple discrete, round to oval masses of 100–300 m (Branch et al., 1971). One patient has been reported presenting with diabetes insipidus. He had a posterior pituitary mass but no other abnormalities in the pituitary, infundibulum and hypothalamus. The mass showed complete repression after corticosteroid treatment, but diabetes insipidus persisted (Loh et al., 1997). The most common MRI abnormality in cases of neurosarcoidosis is the presence of multiple white-matter lesions (Zajicek et al., 1999). MRI may demonstrate hypothalamic periventricular and meningeal lesions (Bell, 1991) and thickening of the pituitary stalk that extends toward the optic chiasm (Walker, 1990). Only rarely does neurosarcoidosis present itself as an intracranial mass lesion. An example is the case described by Grand et al. (1996; Fig. 21.3) with a lesion resembling a “bunch of grapes” on MR images, extending from the right frontotemporal area toward the midline, involving the hypothalamus. The arachnoid covering the optic chiasm,

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Fig. 21.1. Sarcoidosis involving the optic nerve and hypothalamus. Top: T1-weighted coronal magnetic resonance imaging scan showing asymmetrical thickening of the chiasm (solid arrow). Center: Following gadolinium enhancement, an increased signal can be seen in the hypothalamus, third ventricle (open arrow) and meninges (solid arrow), due to sarcoidosis. Bottom: Sagittal cut showing enhancement in the hypothalamus and pituitary stalk (open arrow), with enlargement of the pituitary gland (solid arrow). (From Westlake et al., 1995, Fig. 1 with permission.)

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Fig. 21.2. Sarcoidosis nodules scattered through the hypothalamus (H&E). (From Sheehan et al., 1982, Fig. 3.45 with permission.)

pituitary stalk and floor of the third ventricle may be opaque, thickened and sprinkled with many miliary nodules (Robert, 1962; Vanhoof et al., 1992). Periventricular enhancement indicates active inflammation (Bell, 1991) and involvement of the ependymal lining often leads to complete obliteration of the third ventricle and to hydrocephalus (Robert, 1962; Scott, 1993). (c) Endocrine changes The prevalence of neuroendocrine disturbances due to neurosarcoidosis has a peak around 30–39 years of age. Hypogonadotropic hypogonadism, polyuria and polydipsia are the most frequently occurring symptoms in patients with sarcoidosis of the hypothalamus and pitu-

itary (Murialdo and Tamagno, 2002). Whereas the symptoms of diabetes insipidus were initially attributed to diabetes insipidus caused by vasopressin deficiency (Selenkow et al., 1959; Robert, 1962; Branch et al., 1971; Stern et al., 1985), later studies indicated that they more often result from primary polydipsia and possibly from destruction of the osmoreceptors, without vasopressin deficiency (Bell, 1991). The displacement of the pituitary bright spot to the upper infundibulum in neurosarcoidosis (Walker et al., 1996) correlates with the presence of diabetes insipidus. A patient has been described with diabetes insipidus and a large posterior pituitary mass that was most probably due to sarcoidosis. A complete regression of the posterior pituitary mass was found after corticosteroid therapy, but the diabetes

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Fig. 21.3. (a, b) Sagittal and (c) coronal T1 images after i.v. gadolinium: sarcoidosis of the hypothalamus. Multiple nodular enhancement resembling a “bunch of grapes” in the right temporal lobe; extension toward the hypothalamohypophyseal region. (d) Axial T2 image: lesions of the intermediate intensity signal surrounded by extensive edema. (From Grand et al., 1996, Fig. 2 with permission.)

insipidus persisted and the patient continued to need his intranasal vasopressin therapy during the 12-month follow-up (Loh et al., 1997). Inappropriate secretion of vasopressin has also been described in neurosarcoidosis (Stern et al., 1985). Deficiency of anterior pituitary hormones most often occurs on the basis of hypothalamic dysfunction, although the pituitary might sometimes be primarily involved as well (Selenkow et al., 1959; Robert, 1962; Stern et al., 1985; Graham and James, 1988; Bell, 1991). Patients may have hypothyroidism, hypogonadism, changes in pubic hair and body hair, loss of libido, secondary amenorrhea, hypoadrenalism, panhypopituitaris, increased serum prolactin and, less often, galactorrhea (Robert, 1962; Turkington and MacIndoe, 1972; Stern et al., 1985;

Graham and James, 1988; Verhage et al., 1990; Bell, 1991; Lipnick et al., 1993, Westlake et al., 1995; Molina et al., 2002; Murialdo and Tamagno, 2002; Randeva et al., 2002). However, it should be noted that Munt et al. (1975) were unable to confirm by radioimmunoassay the high incidence of hyperprolactinemia in patients with neurosarcoidosis involving the hypothalamus. Normally, hypoglycemia stimulates rapid increase of hormones such as catecholamines, glucagon, cortisol and growth hormone to act in concert to increase plasma glucose concentration. This action is regulated by the ventromedial region of the hypothalamus. A patient has been described who had complete loss of the counterregulatory response to hypoglycaemia due to a hypothalamic sarcoid infiltration (Féry et al., 1999). 105

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(d) Therapy Administration of oral corticosteroids, 40–80 mg/day, is the usual first line of therapy for neurosarcoidosis, and often corticosteroids are given long-term, despite the absence of controlled studies of their efficacy and the high frequency of serious side effects (Murialdo and Tamagno, 2002; Randeva et al., 2002). Methylprednisolone pulse therapy has also been applied (Molina et al., 2002). In general, neurosarcoidosis is more resistant to therapy than the pulmonary variety and longterm, high-dose corticosteroid therapy is generally not very well tolerated and not very effective. Methotrexate, cyclosporine-A and cyclophosphamide seem to be more effective (Murialdo and Tamagno, 2002). Recently, the TNF- antagonist infliximab has been tried with some success in the treatment of systemic sarcoidosis and in optic disc swelling in sarcoidosis (Katz et al., 2003). However, in over half of the neurosarcoidosis patients the disease progresses despite corticosteroid or other immunosuppressive therapies (Zajicek et al., 1999).

21.2. Multiple sclerosis (MS) and the hypothalamus MS is an inflammatory demyelinating disease of the central nervous system. It is generally a disease of young adulthood with a peak age of onset between 25 and 30 years of age. The initial course of MS is often characterized by spontaneous relapses and remissions, but it can also run a primary progressive course. Although the exact etiology of the disorder is unknown, there is clinical and laboratory evidence suggesting that it is a multicausal disease with genetic, autoimmune and environmental components (Duquette and Girard, 1993). The premenstrual period triggers exacerbations. In fact, 45% of all exacerbations seem to start in this period (Zorgdrager and De Keyser, 2002). There is a decreasing North–South gradient in risk and there are race and sex differences in predisposition (Limburg, 1950; Kurtzke et al., 1979; Sadovnik and Ebers, 1993). Seasonal fluctuations in peak exacerbation rate depend on the region. Exacerbations of optic neuritis and MS have the highest frequencies in spring and the lowest in winter. The seasonal fluctuations are presumed to be related to a dysregulation of interferon- and viral infections (Balashov et al., 1998; Jin et al., 2000). In addition, stressful life experiences are considered to be risk factors (Goodin et al., 1999; Martinelli, 2000). However, an Israeli paper shows that,

contrary to expectation, the number of relapses during a war and the following months may even be significantly lower (Nisipeanu and Korczyn, 1993). Several genetic factors seem to be involved in the risk of developing MS and in the course of the disease. HLA-DRB1*1501 alleles and estrogen receptor polymorphisms are of importance in this connection and may also be the basis of the sex differences in the prevalence of MS (Kikuchi et al., 2002). In addition, single-nucleotide polymorphism (SNP) in interleukin-1 (IL-1), - and in the IL-1 receptor antagonist influence long-term prognosis in MS (Mann et al., 2002). Apolipoprotein E (ApoE) is involved in the transport of lipids necessary for membrane repair, and is encoded by a gene on chromosome 19q13. MS patients with an ApoE 3/4 genotype have a more severe disease course, according to some studies (Fazekas et al., 2000, 2001), while later onset of chronic progressive MS was observed in patients carrying the ApoE2 allele (Ballerini et al., 2000). However, other studies did not find an association between ApoE4 and adverse outcome in MS (Masterman et al., 2002). An SNP haplotype near ApoE is associated with MS susceptibility (Schmidt et al., 2002). Several other polymorphisms have also been implicated in the susceptibility and course of MS (Cocco and Marrosu, 2000). (a) Autonomic, behavioral and neuroendocrine symptoms A number of autonomic and neuroendocrine functions that are often found to be disturbed in MS point to hypothalamic involvement in this disease. Such autonomic functions include disturbed functions of the bowel and bladder, and of sexual behavior (Matthews, 1991; Hulter and Lundberg, 1995; Mattson et al., 1995), as well as sweating, and respiratory and cardiovascular regulation (Anema et al., 1991; Fowler et al., 1992; Howard et al., 1992), disturbed temperature regulation (Lammens et al., 1989; Tsui et al., 2002), such as acute and chronic hypothermia (Sullivan et al., 1987, White et al., 1996) and poikilothermy (Kurz et al., 1998) and sleep disturbances (Campbell et al., 1982; Clark et al., 1992; Ferini-Strambi et al., 1994; Tachibana et al., 1994; Tsui et al., 2002). One patient had asymmetric sweating of the right forehead and shoulder, due to MS lesions in the left hypothalamus (Ueno et al., 2000). An MS patient was described with a new plaque in the hypothalamus who developed acute hypersomnia and undetectable CSF hypocretin levels (Iseki et al., 2002). A significant

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reduction in tremor has been reported among MS patients after subthalamic ventral intermediate nucleus brain stimulation (see Chapter 15.1). However, patient satisfaction with this procedure was variable (Berk et al., 2002). Sexual dysfunction in patients with MS is typically characterized by diminished libido, erectile and ejaculating dysfunction in men, and poor lubrication and anorgasmy in women. Hypersexual behavior and paraphilias are distinctly uncommon in this group of patients, but have been described associated with focal brain lesions in the hypothalamic and septal regions (Frohman et al., 2002). Some endocrine disturbances in MS are also related to hypothalamic alterations. They include: abnormal testosterone levels (Grinsted et al., 1989; Markianos and Sfagos, 1989), which may lead to hypothalamic hypogonadism, decreased libido and impotence, and may be treated with testosterone (Bourdette et al., 1988); hyperprolactinemia, in five of nine cases accompanied by hypothalamic lesions (Kira et al., 1991; Tsui et al., 2002); altered growth hormone and TSH levels (Klapps et al., 1992); and inappropriate antidiuretic hormone secretion (Apple et al., 1978; Tsui et al., 2002). Alpha-melanotropin (MSH) levels are increased in patients with a greater inability score (Catania et al., 2000). A failure of suppression of cortisol levels was observed following dexamethasone treatment (Reder et al., 1987; Grasser et al., 1996; Fassbender et al., 1998; Kümpfel et al., 1999; Then Bergh et al., 1999), indicating a hyperactive hypothalamopituitary–adrenal (HPA) axis. Cortisol levels in postmortem CSF of MS patients are elevated by some 80% in comparison with controls, which is another indication of an increased HPA activity (Erkut et al., 2002). A severe impairment of the ACTH and metapirone test was reported by some authors (Brambilla et al., 1974), while others did not find a difference in the plasma cortisol response to corticotropin (ACTH) in MS patients (Wei and Lightman, 1997; Kümpfel et al., 1999). The latter group also reported lower dehydroepiandrosterone sulfate (DHEAS) secretion in MS patients. It should be noted that the pathophysiology of hypercortisolism in MS seems to be different (see below) from that in depression. MS is presumed to be associated with increased prominence of hypothalamic VP secretion (Michelson et al., 1994; Michaelson and Gold, 1998; cf. Chapter 26.4). Indeed, the entire increase in corticotropin-releasing hormone (CRH)-expressing neurons in MS appeared to be due to an increase in those CRH neurons that colocalize VP (Erkut et al., 1995; Fig. 21.4). Not only do the CRH

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neurons play an essential role in cortisol regulation, they also influence mood (Chapters 21.2b, 26.4), and it is therefore of particular interest that treating relapsing-remitting MS patients with a combination of corticosteroids and the antidepressant moclobemide favors normalization of the HPA axis (Then Bergh et al., 2001). It has been proposed that the pineal gland may be implicated in the relapsing-remitting nature of the disease. Melatonin was even claimed to be able to cause acute exacerbation of symptoms. Abnormal plasma melatonin levels were found in half of the MS patients during exacerbations. Most of them had nocturnal levels that were below the daytime values. There was also a significant relation between melatonin levels, age of onset of symptoms and the duration of illness. Pineal calcification was found in nearly all the MS patients. These observations were hypothesized to be related to the occurrence of seasonal variations in MS, the influence of climatic variables, and the low incidence of MS in African and American black populations (Sandyk and Awerbuch, 1992). Exactly how the pineal function is related to the MS disease process should be investigated further. Since fatigue and sleep disturbances are frequent and disabling symptoms inMS, and because of the presumed disturbed pineal function, we investigated whether these symptoms might be due to disrupted circadian sleep/wake regulation. However, no evidence was found for a generalized circadian disturbance in MS patients, which indicates that the suprachiasmatic nucleus will generally not be seriously affected in this disease (Taphoorn et al., 1993). Vasopressin levels in CSF, but not in plasma, were found to be decreased in MS (Olsson et al., 1987). It is not clear what exactly the source of this diminished amount of CSF vasopressin is, since we did not find an indication for an activity change in the vasopressin neurons of the PVN in MS (Purba et al., 1995). In addition, Michelson and Gold (1998) presume that MS is associated with increased hypothalamic vasopressin secretion and Erkut et al. (1995) showed that the entire increase in the number of CRH-expressing neurons in MS was due to those CRH neurons that coexpress vasopressin. Desmopressin (DDAVP, nasal spray) is a vasopressin agonist that is effective both in the treatment of nocturnal enuresis and in the treatment of increased daytime urinary frequency, which often seriously disrupts work and social activities in MS patients. A side effect of this therapy might be the development of hyponatremia. Although the patient should be warned about the symptoms of side effects due to hyponatremia, i.e. malaise, headache and nausea 107

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(Hoverd and Fowler, 1998), long-term use of DDAVP has been shown to be safe and effective by others (Tubridy et al., 1999). Lower levels of CSF somatostatin have been found in MS patients during relapse, and a strong relationship has been found between cognitive decline and decrease in CSF somatostatin levels (Roca et al., 1999). It is not known which brain area is responsible for the changes in somatostatin levels. (b) Mood changes Although euphoria was mentioned as the dominant emotional change in MS in an old paper (Cottrell and Wilson, 1926), a fact that is generally known in clinics, more recent literature has repeatedly shown that depression is the major mood change in these patients (Rao

Fig. 21.4. Increased numbers of corticotropin-releasing hormone (CRH) and vasopressin (VP) in multiple sclerosis (MS). Numbers of CRH neurons that do not localize VP (CRH-only) or that colocalize VP (CRH + VP) in the PVN of 8 MS patients and 8 controls. Tissue was obtained from the Netherlands Brain Bank (Amsterdam, the Netherlands). Clinicopathological data (mean ± SEM), age, 51.0 ± 3.8 years (MS), 52.6 ± 5.0 years (controls); postmortem delay 12.9 ± 5.6 h (MS), 13.9 ± 3.9 h (controls); fixation time 49 ± 14 h (MS), 36.7 ± 4.3 h (controls); duration of MS, 23 years; primary progressive MS 2/8 and secondary progressive MS, 6/8. Neurons are counted in the PVN after immunocytochemical double-staining of VP and CRH as described (Erkut et al., 1995). The difference in numbers of CRH/VP neurons between the MS and the control group is significant (p = 0.046). (Based upon Erkut et al., 1995, Fig. 3). Note that the increase in CRH-expressing neurons in MS is solely due to an increase in CRH cells coexpressing VP.

et al., 1992). MS patients are frequently depressed, irritable and short-tempered (Dalos et al., 1983; Schubert and Foliart, 1993; Fassbender et al., 1998). There is a significant interaction between the level of neurological impairment and depression in patients with MS (Mohr et al., 1997b). However, comparison of MS patients with a group of traumatic paraplegics as disease controls also showed a significantly higher incidence of emotional disturbances in the MS patients, especially during periods of relapse (Dalos et al., 1983), and a boost of depression in MS may even occur shortly before neurological symptoms develop (Whitlock et al., 1980; Joffe et al., 1987; Minden and Schiffer, 1990; Millefiorini et al., 1992). so that the mood changes do not only seem to be due to the presence of a neurological disability alone. In agreement with this idea, Fassbender et al. (1998) found that both affective and neuroendocrine disorders in MS were related to the inflammatory disease and not to disability. A relationship is presumed between the hyperactive HPA axis (see previous section) and depression in MS and, indeed, a combined treatment with corticosteroids and the antidepressant moclobemide normalizes HPA axis function in relapsing-remitting MS patients (Then Bergh et al., 2001). A relationship has also been observed between MS lesions in the left arcuate fasciculus, i.e. in the suprainsular white matter and depression in MS (Pujol et al., 1997), while major depression is known also to result from left cortical lesions. The higher levels of depression in MS are associated with sleep complaints (Campbell et al., 1992). The very high rate of depression among MS patients does not have a genetic basis (Sadovnick et al., 1996). Although interferon--1B reduces the frequency and severity of exacerbations of MS in patients with the relapsing-remitting form, it also causes flu-like symptoms and increases depression within the first 6 months after starting this therapy. Subsequent treatment of depression improves the adherence to interferon therapy (Mohr et al., 1997a; Walther and Hohfeld, 1999). (c) The HPA axis in relation to susceptibility and recovery As shown by animal models, the HPA axis, which is a central system in the regulation of immune responses (Rivest, 2001), may influence susceptibility to and recovery from MS. Studies on experimental allergic encephalomyelitis (EAE), the most extensively studied animal model of MS (Polman et al., 1986; Pender, 1987;

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Sobel et al., 1988; McDonald, 1994; Rodriguez and Scheithover, 1994), have indicated that the activity of the HPA axis may be crucial in these processes. In certain rat strains, such as the Lewis rat, low corticosteroid levels are accompanied by a high susceptibility to EAE, whereas, once the disease has been established, elevation of corticosteroid levels is required for spontaneous recovery (MacPhee et al., 1989; Sternberg et al., 1989; Mason et al., 1990; Villas et al., 1991; Kuroda et al., 1994). In line with these findings, glucocorticoids, CRH and urocortin are capable of suppressing EAE in Lewis rats (Bolton and Flower, 1989; Poliak et al., 1997). In relation to the possibility that low corticosteroid levels may lead to increased susceptibility to MS, it is of interest to note that, from the fourth decade of life onwards, CRH neurons become gradually more activated (Chapter 8.5b; Figs. 8.26, 8.27). This is also the age at which MS prevalence starts to decline in the population. Both markers for activity of these neurons, the total number of paraventricular nucleus cells and the proportion of VP-expressing CRH neurons show an age-dependent increase (Raadsheer et al., 1994a, b). No data are available as yet on age-related changes in CRH mRNA in the human PVN. As animal experiments have shown that an increased HPA axis activity may lead to decreased susceptibility to EAE, the age-related increase in CRH activity suggests that this may be an important factor leading to decreasing prevalence of MS with age. Data on CRH neuron activity before the age that MS prevalence increases are at present not available. It has been observed that from 12 to 20 years of age the saliva cortisol level gradually increases (Walker et al., 2001), but the peak age of onset occurs one decade later. Of course it is not known whether those young subjects who have lower HPA axis activity are indeed at risk to contract MS. However, the observation that in EAE the HPA axis is six-fold increased in activity and in MS only 2.5 times (Wei and Lightman, 1997) was proposed to point to a relative deficiency of the HPA axis in MS patients. It is questionable, though, whether these observations in two different species with a different time course in the disease process can indeed be compared so easily. However, this possibility agrees with the observation that the insulin-induced cortisol increase in MS patients was lower than in healthy controls (Teasdale et al., 1967). CRH neurons are clearly activated in MS patients, as appears from the 2.4-fold increase in the number of neurons expressing CRH (Purba et al., 1995) and

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the 4.5-fold increase in neurons coexpressing CRH and VP (Erkut et al., 1995; Fig. 21.4). In fact, the latter study showed that the entire increase in CRH cell numbers in MS was due to an increase in those CRH neurons that colocalized VP, which is different from the situation in depression (see Chapter 26.4). VP potentiates both the peripheral and central effects of CRH (see Chapter 8.5). Our data agree with the increase in plasma levels of corticosteroids reported in MS (Millac et al., 1969; Reder et al., 1987; Michelson et al., 1994) and the presence of an enlarged adrenal gland in this condition (Reder et al., 1987, 1994). Moreover, postmortem CSF cortisol level in MS is elevated by 80%. Cortisol levels in CSF appeared to reflect postmortem serum cortisol, since these levels were highly correlated (Erkut et al., 2002). The dexamethasone–CRH-suppression tests indicated hyperactivity of the HPA axis only in primary and secondary progressive MS, while relapsing-remitting patients had response patterns similar to controls (Heesen et al., 2002). The increased HPA axis activity may be seen as an effort to suppress the disease process. Indeed, exogenous corticosteroids improve the rate of recovery from acute exacerbations of MS and attacks of monosymptomatic optic neuritis. However, there is at present no convincing evidence that glucocorticoid therapy reduces the frequency of MS exacerbations or delays the progression of neurological disability (Milligan et al., 1987; Miller et al., 1992; Frequin et al., 1994; Wenning et al., 1994; Andersson et al., 1998). The strong increase in CRHneuron activity thus seems compatible with the idea that the brain defends itself against the disease process (MacPhee et al., 1989), although it is not entirely successful in this. Indeed, an endocrine paper concluded that the HPA axis activation in MS is a reaction to the disease process, since it correlates with a marker for the acute phase response, white blood cell counts and with gadolinium enhancement in MRI (Wei and Lightman, 1997; Fassbender et al., 1998). The enhanced response in the dexamethasone-suppression test in MS correlated with disease activity and with the clinical subtype of MS in such a way that increased HPA axis activity relates to an increased disease activity or severity (Wei and Lightman, 1997; Then Bergh et al., 1999). In agreement with this idea, Millac et al. (1969) and Grasser et al. (1996) found increased cortisol levels in MS only during exacerbations and a heterogeneity of the HPA system function, possibly at the corticosteroid receptor level. Although the presence of a partial glucocorticoid receptor 109

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deficiency in some MS patients can, at present, not be excluded as the reason for a different course of HPA axis activation, there does not seem to be any gross disorder of the HPA axis in MS (Millac et al., 1969). In line with this conclusion is the observation that, after cessation of the corticosteroid therapy for relapses, HPA axis function is normal and corticosteroid replacement therapy seems unnecessary (Miró et al., 1990). In addition, it has been observed that cortisol release induced by the dexamethasone–CRH test, is negatively associated with the presence and number of gadoliniumenhancing lesions and positively associated with ventricular size. This suggests a protective effect of the HPA axis drive on acute lesion inflammation in MS. These observations can, however, also be explained in a different way. The observation that prolonged treatment with prednisolone significantly decreases brain volume (Hoogervorst et al., 2002) is another reason to have reservations about long-term corticosteroid therapy in MS. CRH itself may also be directly involved in the defense against the disease process, because it has a neuroprotective effect (Fox et al., 1993) and immunomodulating actions (Webster et al., 1998). Moreover, CRH has analgesic properties (Lariviere and Melzach, 2000). It is remarkable that the condition of most women with MS stabilizes or improves during pregnancy, but after delivery they run an increased risk of suffering a relapse. It is estimated that the risk that the condition takes a turn for the worse is between 20% and 75%. However, it is not clear what factors determine susceptibility changes during pregnancy and postpartum (Birk et al., 1990), although steroid hormones are presumed to be implicated. Hormonal changes preceding the menstruation may worsen symptoms in a subgroup of women with relapsing-remitting MS (Zorgdrager and De Keyser, 1997). (d) Inflammation, demyelination and hypothalamic structures MS is an immune-mediated disease characterized by inflammatory demyelinating perivascular lesions in the white matter, disseminated in time and space (Raine, 1994). In addition, brain weight is decreased (Jelliffe and White, 1935; Erkut et al., 1995). Although ample literature covers the neuropathology of MS, little reference has been made to the hypothalamus. Hypothalamic lesions as

mentioned by Brownell and Hughes (1962) are said to make up only 1% of the total lesions, which does not agree with our observations, which showed a large number of demyelinated plaques to be present in hypothalamic and adjacent structures in a high proportion of MS patients (Huitinga et al., 2001). Moreover, acute unilateral optic neuritis is generally not included in “hypothalamic involvement”, while, within 5 years, in some 30% of patients, it was followed by clinically definite MS. Corticosteroids did not influence this risk, nor the degree of neurological disability in a 5-year follow-up study (Optic Neuritis Study Group, 1997). Unilateral optic neuritis occurs often as an initial manifestation of MS. Acute bilateral optic neuritis is less common. Swelling and demyelinating lesions in myelinated bundles can be shown by MRI, also following gadolinium enhancement (Fig. 21.5), and pathology has confirmed the inflammatory nature and demyelination. The optic radiations are almost always involved (Newman et al., 1991; McDonald and Barnes, 1992). MS lesions are mentioned by Bignani (1961) and Peters-Bonn (1958) to be present not only around the walls of the lateral ventricles, but also around those of the third ventricle. Early periventricular lesions are situated around subependymal veins, causing focal perivenous demyelination. The lesions subsequently coalesce with neighboring lesions (Adams et al., 1987). A limited number of other papers mentions the involvement of the hypothalamus in MS: Zimmerman and Netzky (1950) found that the paraventricular nucleus of the hypothalamus is sometimes involved in MS; Bignani et al. (1961) described fresh plaques throughout the whole hypothalamus in a patient with a depression, profuse sweating and hyperthermia. An MS patient has been described with acute relapses associated with drowsiness and hypothermia. Although MRI, endocrine and autonomic studies failed to localize a lesion in the hypothalamus, subsequent necropsy showed plaques of demyelination throughout the hypothalamus, including the area of the posterior hypothalamic nucleus (White et al., 1996). In addition, a woman with MS who had presented with hypothermia, dysphagia, lethargy, dysrhythmicity and bronchopneumonia, showed a large, mature, gray, translucent gliotic plaque involving the hypothalamus at the postmortem. At the microscopic level, there was evidence of current activity in a proportion of that plaque. In addition to gliosis, lymphocytic cuffing of vessels and occasional macrophages containing lipid debris were seen (Edwards et al., 1996a). Kamalian et al. (1975) reported a malignant case of MS in which the disease began with

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in body temperature, depression and an activated HPA axis (see above) we investigated the possible presence of MS lesions in 16 MS patients using myelin Klüver– hematoxylin staining, CR3/43 (anti-HLA-DR, -DP, -DQ) as a marker for activated microglial cells (Graeber et al., 1994), glial fibrillary acidic protein (GFAP, marker for astrocytes), KP1 (recognizes macrophages and microglial cells) and amyloid precursor protein (APP, detects axonal damage; Ferguson et al., 1997). The myelinated bundles in and around the hypothalamus analyzed were the optic system (optic nerves, optic chiasm and optic tract), the fornix, internal capsule and anterior commissure. We distinguished between active demyelinating lesions containing foamy macrophages and microglial cells and chronic, inactive hypocellular gliotic lesions (De Groot et al., 2001; Huitinga et al., 2001; Figs. 21.6–21.10). The hypothalamus of 16 of 17 MS patients contained demyelinated lesions (Fig. 21.6). The incidence of active lesions was high (60%) and outnumbered chronic inactive gliotic lesions in the internal capsule. In 4 out of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients gray matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score. Since comparison of hypothalamic lesions with MS

rapid weight loss and terminated after 17 months with generalized muscle wasting and cachexia. Demyelinating lesions were found in the lateral hypothalamus and a relationship was proposed between the clinical symptoms and the localization of the lesions, because lesions in the lateral hypothalamus may cause aphagia and anorexia (see Chapter 23). The optic nerves and chiasm were almost completely demyelinated and there was intense reactive astrogliosis. The fornix showed a patchy loss of myelin. A plaque-like sclerotic lesion was located in the left lateral hypothalamus. The plaque showed almost complete loss of myelin, a moderate, diffuse astrogliosis and occasional small lymphocytic infiltrates. The right lateral hypothalamus showed slight myelin loss. The dorsomedial and ventromedial nuclei appeared to be unaltered. An old plaque with its pronounced fibrillary astrogliosis continued into the left mamillary body and fornix, surrounded by more cellularly active lesions. There were also subacute lesions with perivascular infiltrates along the third ventricle. In MS patients with hyperprolactinemia, hypothalamic lesions were present in 5 of 9 patients (Kira et al., 1991; Tsui et al., 2002). Because MS patients show “hypothalamic signs and symptoms” such as fatigue, sleep disturbances, changes

Fig. 21.5. Multiple sclerosis patient with optic chiasmal neuritis. MR. T1-weighted images after gadolinium enhancement. Coronal (A) and axial (B) views demonstrating a thickened optic chiasm with focal enhancement (arrows). (From Newman et al., 1991, Fig. 2 with permission.)

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Fig. 21.6. Multiple sclerosis (MS) lesions in the human hypothalamus. A and B: Kluver staining of the hypothalamus of a control subject (82016, (A) and a MS patient (93-051, (B). Myelin is stained blue. Note that, in the control subject the myelinated bundles (IC: internal capsule, FX: fornix, OS: optic system) can easily be distinguished, whereas, in the MS patient, myelin bundles contain large white spots or are even barely visible (i.e. the OS in MS patient 93-051) because of demyelinating MS lesions (*). In the control subject, the anterior commissure (AC) is not present at this level. The left FX in the MS patient is partly demyelinated. IF: infundibulum, P: PVN. Magnification: 4.5 . C and D: Human leukocyte antigen (HLA-DR, -DP, -DQ) staining of an active MS lesion in the internal capsule in MS patient 95-065 (C) and a (p)reactive lesion also in the internal capsule of MS patient 96-026 (D). Note the foamy character of the HLA-positive macrophages in the active lesion in (C), indicative of myelin phagocytosis, and the ramified character of the HLA-positive macrophages in the (p)reactive lesion in (D), indicative of activated microglial cells. Arrow points at perivascular leukocyte cuffing. Magnification: 400 . bv = blood vessel. Tissue was obtained from the Netherlands Brain Bank. (From preparation by I. Huitinga.)

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disease severity in MS (Schrijver et al., 1999) and because priming with IL-1 suppresses EAE in the Lewis rat (Huitinga et al., 2000b). Since demyelinating lesions in fiber bundles in and adjacent to the hypothalamus (i.e. the fornix, anterior commissure, internal capsule and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients, we investigated the relationship between the presence of hypothalamic lesions and the state of activation of CRH neurons in MS patients (n = 15). The state of activation of CRH neurons was determined by quantifying the number of CRH neurons that did or did not contain vasopressin, as well as the amount of CRH mRNA expressed in the paraventricular nucleus. The state of activation of CRH neurons in the MS group was compared with that in controls (n = 14). Hypothalamic MS lesions were determined as described above. As found previously (Erkut et al., 1995; Purba et al., 1995), numbers of CRH neurons that colocalize vasopressin are significantly increased in MS. In line with these findings we also found increased levels of CRH mRNA in MS. Interestingly, there was a strong, significant negative relationship between the numbers of CRH neurons that colocalize vasopressin (the population of CRH neurons that is increased in MS) and active MS lesions in the hypothalamus. There was no relation between CRH single positive neurons and the active lesion score. The effect was thus neuron-specific. The chronic inactive lesion score did not correlate with the numbers of CRH that colocalize VP in MS; the effect thus concerns only the immunologically active lesions. The same negative relationship was seen between the amount of CRH mRNA expression and the active lesion score in MS. This relationship, too, concerned only immunologically active lesions and not the chronic inactive gliotic lesions. Interestingly, controls also showed a negative relationship between HLA score (activated microglial cells) and the amount of CRH mRNA expression, indicating that the relationship between activated microglial cells and the decreased activation of CRH neurons is not MS specific. Thus, whereas as a group MS patients have activated CRH neurons, the presence of active lesions and activated macrophages and microglial cells in or around the hypothalamus of MS patients induces a significant decrease in the activation of CRH neurons. Apparently, MS patients with many active lesions in the hypothalamus have a diminished activity of the HPA system (Huitinga et al., 2002). The clinical consequences of such an impaired activity of the HPA

Fig. 21.7. Active and chronic inactive lesion scores (bars) and the incidence of active and chronic inactive lesions per fiber bundle (numbers on top of the bars) in the hypothalamus of multiple sclerosis patients: the internal capsule (IC), anterior commissure (AC), fornix (FX) and optic system (including optic nerve and optic chiasm, OS). Note that the AC and the FX were not present in the sections studied in all patients. The active lesion score includes (p)reactive and active lesions and the chronic inactive lesion score includes only chronic inactive hypocellular gliotic lesions. Bar represents the mean ± SEM. (From Huitinga et al., 2001, Fig. 2 with permission.)

lesions in other areas of the brain in the same patients (n = 7) showed a great similarity as both stage and appearance were concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen, but, in 11 control cases, HLA expression was observed that was lower than in MS patients. Thus, systematic pathological investigation of the hypothalamus in MS patients reveals an unexpectedly high incidence of active lesions. Preactive lesions were also found in the neurosecretory supraoptic nucleus (SON) (Fig. 21.11). In the oxytocin neurons of the PVN and accessory nuclei, IL-1 was found (Fig. 21.12). In MS patients fewer neurons in the PVN were found to be positive for this cytokine (Huitinga et al., 2000a; Fig. 21.13). This finding may be of particular interest in relation to MS, since a specific combination of IL-1 and IL-1 receptor antagonist is associated with 113

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Fig. 21.8. Microphotographs of multiple sclerosis (MS) lesions. A: CD68-positive foamy macrophages in an active lesion in the internal capsule (IC) of MS patient 95-065. B: Klüver staining of an active lesion in the OS of MS patient 95-065. Arrows point at two foamy macrophages at the edge of the lesion. Arrowheads point at luxol fast blue-positive particles in the macrophages. C: Gliosis in a chronic active lesion in the IC of patient 95-065. Arrows point at glial fibrillary acidic protein (GFAP)-positive hypertrophic astrocytes. D: human leukocyte antigen (HLA-DR, -DP, -DQ)-positive microglial cells (arrow) and HLA-positive leukocytes (arrowhead) in the Virchow–Robin space around a blood vessel (Bv), indicative of a (p)reactive MS lesion in the IC of MS patient 96-026. E: A chronic inactive lesion in the OS of patient 93-051. Arrows point at HLA-DR, -DP, -DQ-positive microglial-like cells and arrowheads point at isomorphic gliosis and widened extracellular spaces typical for gliotic tissue. F: Perivascular accumulation of CD3-positive T cells near an active lesion in the IC of patient 95-065. Bar = 15 m. (From Huitinga et al., 2001, Fig. 3 with permission.)

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Fig. 21.9. Microphotograph of axonal damage and HLA expression in the supraoptic nucleus (SON) and the median eminence. A: Bodian staining of the optic system (OS) of MS patient 93-051. Note the reduced density of axons as compared to the axonal density in Fig. B. B: Bodian staining of the OS of MS patient 96-026. There is no sign of axonal damage in the OS of this MS patient. C: amyloid precursor protein (APP)-immunoreactive axons in the IC of MS patient 91-070. Note the large-diameter (5–7 m) of the APP-immunoreactive axons. Adjacent to this area is an active MS lesion (not shown). D: HLA-DP, -DQ, -DR-positive microglial cells in the SON of MS patient 96-026. Arrow points at an HLA-positive microglial-like cell that seems to be in close contact with an SON neuron. E: HLA-DR, -DP, -DQ-immunoreactive microglial-like cells in the median eminence of control 93-085. Arrows point at HLA-reactive microglial-like cells in close vicinity of blood vessels (Bv). F: HLA-DR, -DP, -DQ-immunoreactive cells in the median eminence of MS patient 95-095. Arrow points at a small lesion of HLA-positive cells. Bar = 15 m. (From Huitinga et al., 2001, Fig. 4 with permission.)

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Fig. 21.10. The relationships between the duration (in years) of multiple sclerosis (MS) and the active lesion score (left panel, p = 0.001, r = –0.719) and chronic inactive lesion score (right panel, p = 0.102, r = –0.410) in the hypothalamus. Note that there is a significant inverse correlation between the active lesion score and the duration of MS, i.e. leading to death, but not between the chronic inactive lesions score and the duration of MS. (From Huitinga et al., 2001, Fig. 5 with permission.)

system in a subgroup of MS patients should be studied further. (e) Differential diagnosis of optic neuritis Acute optic neuritis in MS should be differentiated from Leber’s hereditary optic neuropathy. In children, optic neuritis is often bilateral. It usually follows infections such as measles, chicken pox and infectious mononucleosis in nearly half of cases, and there is a seasonal fluctuation, with the greatest number presenting in April. While the risk of MS after childhood optic neuritis is low (some 15%), the risk factor for adults is 75% (McDonald and Barnes, 1992). The diagnosis of MS has often been applied to patients with a syndrome that has recently been renamed recurrent optic neuromyelitis with endocrinopathies. It has been described in Antillean women from Martinique and Guadeloupe. Myelopathic symptoms and visual problems recurred. Spinal cord involvement consisted of a band-like sensory loss and MRI shows caviation-like images. The endocrinopathies consisted of amenorrhea, galactorrhea,

diabetes insipidus, hypothyroidism or hyperphagia. In the spinal cord, demyelinizing lesions with diffuse spongiosis are found with thickened blood vessel walls without evidence of inflammation. Autonomic abnormalities are present in half of cases. Demyelination of the optic tracts is observed; the optic neuromyelitis is probably of postinfectious origin. In three cases MRI revealed lesions in the pituitary and inferior hypothalamus (Vernant et al., 1997). 21.3. Langerhans’ cell histiocytosis (Hand–Schüller–Christian disease; histiocytosis-X) Hand–Schüller–Christian disease, with its granuloma that are preferentially located in the hypothalamus and pituitary (Gagel, 1941; Treip, 1992; Fig. 21.14) is also known as Langerhans’ histiocytosis or histiocytosis-X (Kepes and Kepes, 1969; Schneider and Güthert, 1975). The terms Gagel’s granuloma, eosinophilic granuloma, Ayala’s granuloma, Letterer–Siwe disease and hypothalamic granuloma have all been used (Horvath et al., 1997;

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Fig. 21.11. Microphotograph of a (p)reactive lesion in the optic nerve (on) and in the supraoptic nucleus (son) in multiple sclerosis (MS) patient 96-307. A: HLA-DP, -DQ, -DR-positive cells in the ON and SON (arrowheads point at HLA-DP, -DQ, -DR-negative SON neurons) in section 601. B: Interleukin-1(IL-1)-staining of section 599. The same area as in A, containing the son and a rim of the on. Arrowheads point at IL1-negative and the arrow points at an IL-1-positive neuron in son. In the on, arrowheads point at IL--ir glial cells. C: Magnification of HLA-DP, -DQ, -DR-positive cells in the on; D: magnification of interleukin-1 (IL-1)-ir cells in the on. Note: in the gray matter in the son, as well as in white matter in the on, HLA-DP, -DQ, -DR-ir glial cells are present that are indicative of a (p)reactive MS lesion in both areas, whereas IL-1-ir cells are only present in the on and not in the son. Bar: 45 m in A, B; 15 m in C, D. (From Huitinga et al., 2000a, Fig. 4 with permission.)

Rosenzweig et al., 1997). The disease may represent an uncontrolled immunological reaction to an unknown antigen (D’Avella et al., 1997; Schmitz and Favara, 1998). In a very small number of families, recurrence of the disease has been reported (Arico and Egeler, 1998). There is a unifocal benign form of the disease in which the hypothalamus and pituitary are spared. It is characterized by a solitary lytic bone lesion. The multifocal form is more aggressive and, in childhood, presents with the

clinical triad – diabetes insipidus, exophthalmus and lytic bone disease – secondary to granulomas in the hypothalamus and pituitary gland. On MR images the pituitary stalk is thickened symmetrically. However, after a few years there is a complete reversal of the pituitary stalk enlargement in a large percentage of the patients. The normal high MRI signal density in the posterior lobe is frequently absent. Associated involvement of the temporal bone supports the diagnosis (Chong and Newton, 117

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Fig. 21.12. Microphotograph of interleukin-1 (IL-1)-ir neurons in the paraventricular nucleus (PVN) in two control cases and two multiple sclerosis (MS) patients illustrative of IL-1 staining intensity in the control versus the MS group. Per patient the rank number in estimated numbers of IL-1-ir PVN neurons in the group (see Fig. 21.13) are given in parentheses: A: control 96-163 (3rd), B: MS 90-246 (1st), C: control 96-019 (9th), D: MS 96-352 (9th). Arrows point at IL-1-positive neurons containing a nucleolus and arrowheads point at IL-1-negative neurons containing a nucleolus. Bar = 15 m. (From Huitinga et al., 2000a, Fig. 6 with permission.)

1993; Fig. 21.15; Rami et al., 1998; Leger et al., 1999; Czernichow et al., 2000). The classic triad of diabetes insipidus, exophthalamus and lytic bone disease is present in only 25% of the cases. Visual disturbances and endocrine dysfunctions such as delayed or precocious puberty, hypogonadism, growth retardation, growth hormone deficiency in the insulin hypoglycemic tolerance test, hypothyroidism, hypoadrenalism, panhypopituitarism, diabetes insipidus, morbid obesity and modest hyperprolactinemia may also be present (Ober et al., 1989; Chong and Newton, 1993; Lin et

al., 1998; Rami et al., 1998; Modan-Moses, 2001; Beswick et al., 2002; Harris et al., 2002). A few cases with polyneuropathy have been described. One such an atypical case is a patient with Langerhans’ cell histiocytosis and polyneuropathy, diagnosed 12 years after the development of diabetes insipidus following head trauma (Malkoç et al., 2000). A girl with Langerhans cell histiocytosis developed diabetes insipidus and central precocious puberty at 7.5 years of age (Municchi et al., 2002). In a late stage of the disease, vegetative disorders, short-term memory deficits, psychic disturbances, disor-

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since then agreement has been reached about the role of the Langerhans cell, a cell with features similar to the Langerhans’ cell of the epidermis, which is now considered to be the principal proliferating cell in the disease (Ober et al., 1989; Schmitz and Favara, 1998). The normal epidermal Langerhans cell is a dendritic, antigenpresenting cell characterized by the intracytoplasmic, tennis racket-shaped Birbeck granule of 200–400 nm in width and by expression of CD1a and S-100. Tissue damage is caused by excessive production of cytokines and prostaglandins (Rosenzweig et al., 1997). Lymphocytes and plasma cells, eosinophils, giant cells and microglia are also found. In one case – an adult male with Langerhans’ cell histiocytosis – diabetes insipidus occurred 5 years before the skin lesions and the hypothalamic mass became evident (Catalina et al., 1995; Horvath et al., 1997). By using positron-emission tomography (PET), both increased and decreased glucose metabolism was found in cases of Langerhans cell histiocytosis. The increased activity probably represents an active, ongoing disease process, and areas of decreased activity either represent a burnt-out brain lesion caused by the disease or a decreased brain metabolism of other origin (Calming et al., 2002). An unusual case of isolated histiocytosis presented as a solitary mass in the pineal gland with incomplete ocular palsy (Gizewski and Forsting, 2001). Spreading may occur through portal vessels or via the systemic circulation (Wilke, 1956). A primary phase of histiocyte proliferation is followed by brain atrophy or demyelination and gliosis of unknown origin (Barthez et al., 2000). Apart from corticosteroids (Harris et al., 2002), chemotherapy and low-dose radiotherapy have been reported to be successful treatments for Langerhans’ cell histiocytosis masses in the hypothalamus (Catalina et al., 1995). At least in those patients with shortterm polyuria or polydipsia, and with an abnormality in water-deprivation tests, rapid treatment with hypothalamopituitary radiation therapy seems justified. However, there seems to be no rationale for treating patients with full diabetes insipidus, as there is no evidence that patients in later stages of the disease will respond to this therapy (Rosenzweig et al., 1997). Although chemotherapy may cause a regression of the Langerhans’ cell histiocytosislesion, even in some cases with good therapeutic results, hormone deficiencies are usually irreversible (Rami et al., 1998). In the case of a solitary hypothalamic granuloma, where Langerhans’ cell histiocytosis was found with diabetes

Fig. 21.13. Total numbers of interleukin-1-immunoreactive (IL-1-ir) neurons in the paraventricular nucleus (PVN). Bars indicate the median. Triangles indicate individual cell counts. Note the high interindividual variation. The total number of IL-1-ir neurons in the PVN was significantly decreased in the multiple sclerosis (MS) group as compared to the control group (p < 0.05). In addition to the reduction in numbers of IL-1-ir neurons in the PVN, also the IL-1 staining intensity was strongly reduced in most MS patients. (From Huitinga et al., 2000a, Fig. 7 with permission.)

ders of temperature regulation and hypersomnolence have been described (Schneider and Güthert, 1975; Yen, 1993; Kaltsas et al., 2000). The disorder may have a waxing and waning course. About 50% of the patients with hypothalamic diabetes insipidus due to histiocytosis-X had antibodies against VP neurons. In a patient who became pregnant, diabetes insipidus remitted at about the 28th week of gestation and recurred after delivery. Improvement of the disease during pregnancy supports the notion of an autoimmune pathogenesis (Scherbaum, 1992). The disease is neuropathologically characterized by infiltration of the hypothalamus and pituitary, including the pars distalis by lipid-laden histiocytes or foam cells that appear to be involved in the autoimmune process (Scherbaum et al., 1986). Autoimmunity to hypothalamic vasopressin cells may be present in a large percentage of patients with central diabetes insipidus and Langhans’s cell histiocytosis (Pivonello et al., 2003). The ‘X’ in the term histiocytosis-X indicated an “unknown cell”, but 119

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Fig. 21.14. Gagel granuloma (Langerhans’ histiocytosis). Sagittal section of the pituitary gland, showing enlargement of the stalk and posterior lobe (on the right) by granulomatous infiltration. Hematoxylin & eosin.  5.5. (From Treib et al., 1992, Fig. 16.11 with permission.)

insipidus and panhypopituitarism, complete microsurgical excision was performed (D’Avella et al., 1997). Some clinicians advocate the combination of surgical excision with postoperative radiation (Çolak, 1998). However, surgical resection and chemotherapy with prednisolone and vinblastine have also been effective (Lin et al., 1998). Dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) (Lin et al., 1998; Maghnie et al., 1998b). Erdheim–Chester disease, first described in 1930 as lipoid granulomatosis, is a rare condition, predominantly

of middle-aged males. The pathological hallmark of this disease consists of xanthogranulomatous infiltrations of a wide variety of tissues by cells of macrophage or histiocyte lineage. Symmetrical predominantly sclerotic bone lesions sparing the epiphysis and the predominance of lipid-laden histiocytes or foam cells in the patient’s retroperitoneal tissues was considered as a diagnostic of Erdheim–Chester disease. This entity is distinct from histiocytosis-X, but the two diseases may represent a disease spectrum. Patients have been described with multiorgan involvement, thrombocytopenia, central diabetes insipidus, panhypopituitarism, hyperprolactinemia, gonadotropin insufficiency, decreased insulin-like growth factor

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Fig. 21.15. Histiocytosis. Sagittal (A) and coronal (B) precontrast and postcontrast-enhanced MR scans. The pituitary stalk (arrows) is markedly enlarged. Prominent contrast enhancement of the stalk is noted. (From Chong and Newton, 1993, Fig. 23 with permission.)

I levels and bilateral adrenal enlargement, suggesting hypothalamic-pituitary dysfunction. The high-intensity signal of the posterior pituitary on T1-weighted images may be absent on MR images, the pituitary stalk and dura may be thickened and a hypothalamic mass has been described. The diagnosis of the rare cranial localizations is usually made on the basis of a biopsy (Tritos et al., 1998a; Oweity et al., 2002; Perras et al., 2002).

21.4. Other neuroimmunological hypothalamic disorders and lesions The idiopathic hypothalamic dysfunction syndrome of childhood (Chapter 32.1) may be based upon a nonmetastatic paraneoplastic syndrome related to the presence of an occult neural-crest tumor. The tumor probably produces antineuronal antibodies that lead to extensive 121

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Fig. 21.16. Granular ependymitis of the third ventricle in a case of sudden death (NHB 96-077, 68). Bar = 400 m.

lymphocytic/histocytic infiltrates in the hypothalamus and other brain areas. Lymphocytic hypophysitis and autoimmune diabetes insipidus are discussed in Chapter 22.2. Granular ependymitis are periventricular lesions characterized by raised pyramidal granulations with focal gliosis in the subependymal region. The overlying ependyma is trophic, eroded or absent (Fig. 21.16). Some of the cases with ependymitis or subependymal gliosis are active, in the sense that they contain lymphocytic

infiltrates. Granular ependymitis is generally associated with ventricular dilatation or meningitis. Although granular ependymitis is more frequently seen in MS, it is certainly not specific for this disease and also found in, e.g. Parkinson’s disease, vascular disease and senile atrophy. In addition, it is found in, e.g. meningococcal or pneumococcal meningitis. In MS, granular ependymitis may provide a possible route for the exchange of inflammatory agents between the brain and the CSF (Adams et al., 1987).

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infections such as viral encephalitis, i.e. following infections with the Epstein-Barr or the Varizella zoster virus (Merriam 1986; Fenzi et al., 1993; Salter and White, 1993; Müller et al., 1998b). Perivascular inflammatory infiltrates and microglial proliferation of nodular type were observed in the hypothalamus (Fig. 28.1), in particular the floor of the third ventricle and in the periaqueductal gray. In two previous cases, inflammatory changes were present in the hypothalamus and in the temporal lobe or they were confined to the thalamus. Prevalence of T-lymphocytes in the affected area was suggestive of an unknown viral antigen responsible for the immuneresponse and is consistent with the observation that in 35% of the Kleine–Levin cases the onset is preceded by respiratory disease or vaccination (Fenzi et al., 1993). In addition, the increased (HLA)DQB1*0201 allele frequency was significantly increased in Kleine–Levin syndrome. This, together with the young age of onset, the recurrence of symptoms and the frequent infectious precipitating factors suggests an autoimmune etiology for Kleine–Levin syndrome (Dauvilliers et al., 2002).

In Guillain–Barré syndrome, inappropriate vasopressin secretion (Chapter 22.6a) and undetectable CSF levels of hypocretin (Ripley et al., 2001; Kanbayashi et al., 2002; Chapter 28.4) have been described, pointing to hypothalamic involvement. Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia. It is due to antineuronal antibodies. Patients with anti-Ta (anti-Ma2) antibodies frequently have hypothalamic involvement, as appears, e.g. from diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism. The tumor should be treated (Gultekin et al., 2000; Chapter 19.1b, 32.1). For the possible autoimmune destruction of the orexin/hypocretin system in the lateral hypothalamus in case of narcolepsy, see Chapter 28.4. In anorexia and bulimia nervosa patients, autoantibodies against -MSH, ACTH and luteinizing hormonereleasing hormone (LHRH) have been found (Fetissov et al., 2002; Chapters 22.2b, 23.2), but their function has not yet been elucidated. Kleine–Levin syndrome (periodic somnolence and morbid hunger, see Chapter 28.1) may follow viral

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